3-h-1,4-benzodiazepin-2(1h)-ones and their preparation



United States Patent Office 3,412,086 Patented Nov. 19, 1968 Thisapplication is a continuation-in-part of application Ser. No. 182,133,(now abandoned), filed Mar. 23, 1962, which application is acontinuation-impart of applications Ser. No. 103,727 filed Apr. 18, 1961and Ser. No. 2,605 filed Jan. 15, 1960, (now abandoned).

This invention relates to Z-amino-trifluoromethyl-benzophenones as Wellas precursors and derivatives thereof. More particularly, the inventionrelates to compounds of the structural formula wherein R is chosen fromthe group consisting of hydrogen, lower alkenyl and lower alkyl, R; andR are chosen from the group consisting of hydrogen, halogen, nitro,amino and trifluoromethyl; and at least one of R and R istrifluoromethyl.

The invention relates also to the compounds which are intermediates forthese amino-benzophenones and to the compounds which can be producedfrom them.

Z-amino-trifiuoromethylbenzophenones are especially valuable for thesynthesis of benzodiazepine compounds, e.g. compounds represented by oneof the following formulas wherein A represents a carbon nitrogengrouping which completes the seven-rnernbered diazepine ring and whichis selected from the group consisting of R is selected from the groupconsisting of hydrogen, lower alkyl and lower alkenyl; R R and R eachrepresent a member of the group consisting of hydrogen and lower alkyl,R, and R are chosen from the group consisting of hydrogen, halogen,nitro, amino and trifiuoromethyl; and at least one of R and R istrifluoromethyl. In a preferred aspect, R is joined to the 5 phenyl ringat the ortho position thereof.

These compounds (i.e., those of Formulas II and III above) are valuabletherapeutic agents. In addition to the compounds within the scope ofFormulas II and III above there are also encompassed by the inventionthe pharmaceutically acceptable salts of said compounds. Certaincompounds of the above formulas form pharmaceutically accep'table acidaddition salts and/or pharmaceutically acceptable quaternary ammoniumsalts. Thus, the basic benzodiazepine compounds (i.e. those of FormulasII and III above except those illustrated by Formula VI below) of theinvention form acid addition salts by reaction with inorganic andorganic acids such as mineral acids, e.g. hydrohalic acids, for exampleby hydrochloric acid, hydrobrornic acid and the like, nitric acid,sulfuric acid, phosphoric acid, etc. and acetic acid, methanesultonicacid, succinic acid and the like. Also the compounds containing atertiary amino nitrogen atom in the 4-position, i.e. the compounds ofFormulas II and III wherein R is lower alkyl, form pharmaceuticallyacceptable quaternary salts with conventional quaternizing agents suchas lower alkyl halides and the like.

The compounds formed during the synthesis of the trifluoromethylbenzophenone and those formed during the preparation of thebenzodiazepines are novel compounds which, except as pointed out below,are within the scope of this invention.

The 2-amino-trifiuoromethylbenzophenone compounds of the invention canbe produced by a variety of methods, which are illustrated in detail inthe examples to follow. One method involves the reaction of ananthranilic acid derivative with acetic anhydride to produce a 2-methyl-3,1-benzoxazin-4-one. By reacting this latter compound with a phenylGrignard agent and hydrolyzing the resulting crude product, the desiredZ-amino-trifluoromethylbenzophenone can be obtained. When an anthranilicacid starting material bearing a tritiuoromethyl substituent is used,the ring bearing the Z-amino substituent in the benzophenone issubstituted by a trifluoromethyl group. However, if the phenyl Grignardagent is substituted by a trifluoromethyl group, then the benzophenonebenzene ring which does not contain the Z-amino group will betrifluoromethyl substituted. Also a 3,1-benzoxazin-4-one, derived from atrifluoromethyl-substituted anthranilic acid, can be reacted with atrifluoromethyl-substituted phenyl Grignard agent to yield a2-amino-bis(trifiuoromethyl)benzophenone.

An alternative method of obtaining the 2-aminotrifiuoromethylbenzophenone compounds is to react a 2- chlorobenzonitrilewith a phenyl Grignard agent, e.g. with a phenyl magnesium halide orphenyl lithium. This reaction produces a 2-chlorobenzophenone iminewhich, upon acid hydrolysis, yields a 2-chlorobenzophenone, saidcompound yielding the desired Z-aminobenzophenone upon ammonolysis. Ifthe 2-chlorobenzonitrile starting material has a trifluoromethylsubstituent then the benzene ring containing the 2-a'mino substituent inthe benzophenone end product will be trifiuoromethyl substituted.

The Z-arnino-trifiuoromethylbenzophenones can be converted with glycineor an ester thereof to form trifluoro- 3 methyl-5-phenyl-3H-l,4-benzodiazepin-2( 1H) -ones which have the structural formula R I IIwherein R R and R have the same meaning as above.

If, instead of glycine or its ester, a longer chain a-amino acid orester thereof is used, for example u-alanine or its ester, then asubstituent can be introduced into the 3-position, e.g.

OIL-R2 R5 wherein R R R and R have the same meaning as above.

Alternatively, 2 amin0-trifluoromethylbenzophenones can be treated withhydroxylamine hydrochloride to form corresponding2-arnino-trifluoromethylbenzophenone oxirnes. Reaction of the oxime withchloroacetyl chloride in acetic acid produces the chloroacetamino.derivative which cyclizes to form a 2-chloromethyl-4-phenylquinazoline3-oxide bearing a trifluoromethyl substituent. The last named compoundcan then be reacted with an alkali metal hydroxide or alkaline earthmetal hydroxide, preferably in an inert organic solvent such as alcohol,acetone, dioxane, and the like, to enlarge the ring and produce a5-phenyl-3H-1,4-benZodiazepin-2(1H)-one 4- oxide bearing atrifluoromethyl substituent and having the structural formula V whereinR and R have the same meaning as above,

or it can be reacted with ammonia or lower alkylamine to yield a2t-amino-5-plrenyl-3I-I -1,4-benzodiazepine 4 oxide or a 2-loweralkylamino-S-phenyl-3H-1,4-benz0diazepine 4-oxide respectively. Thelatter two products can be represented by the structural formula whereinR R and R have the same meaning as above.

The compounds of Formula VI can be converted to the correspondingcompounds of Formula IV by treatment with phosphorus trichloride or bycatalytic hydrogenation, for example in the presence of Raney nickel. Bythe same procedures, compounds of Formula VH can be converted intocompounds represented by the formula VIII wherein R R and R have thesame meaning as above. When 5-phenyl-3H-1,4-benzo-diazepine compounds,i.e. compounds of Formulas IV, V and VIII above, are reduced withhydrogen in the presence of a platinum catalyst, the corresponding5-phenyl-4,5-dihydro-3H-1,4-benzodiazepines are obtained, i.e. thosecompounds of Formulas II and III wherein A represents are produced.

The compounds corresponding to Formula II (i.e. Formulas IV, V and VI)wherein R is hydrogen and those corresponding to Formulas II and III,wherein R iS hydrogen can be modified so that R and/or R are lower alkylby a variety of methods. Compounds of Formula 11 wherein R is loweralkyl can be obtained by reacting corresponding compounds wherein R ishydrogen with a diazo-alkane, alkyl sulfate or alkyl halide, in a mediumsuch as ether, benzene, alcohol or dioxane. Further, the compounds ofFormula H wherein R is lower alkyl can be obtained directly from2-(N-lower alkyl)-aminobenzophenones. Compounds of Formula II wherein Ris lower alkyl and R is hydrogen can be converted into roccespondingcompounds wherein R is lower alkyl by reaction with a lower alkylhalide. By alkylation of compounds of Formula II wherein R and R areboth hydrogen and by altering the conditions of the reaction, any one offour reaction products can -be obtained. More explicitly, the fourreaction products which can be obtained are those wherein the 1-positionhydrogen alone is replaced, those where the 4-position hydrogen alone isreplaced, those where both the 1- and 4-position hydrogens aresimultaneously replaced and those where the 4- position nitrogen isquaternized. Thus, treatment of a solution of a compound of Formula II,wherein A is and both R and R are hydrogen, with an excess of loweralkyl halide gives the corresponding derivative wherein R is convertedto lower alkyl, while prolonged heating results in the quaternization ofthe 4-position nitrogen atom. On the other hand, by using sodiummethoxide, sodium hydride or the like, to form the sodio derivative ofthe l-position nitrogen atom, and reacting this with an equivalentamount of lower alkyl halide, the corresponding compound of Formula IIwherein only the l-position nitrogen atom is substituted is obtained.Using an excess of lower alkyl halide and prolonged heating with a sodioderivative of a compound of Formula II wherein either both R and R arehydrogen, or wherein R alone is hydrogen, results in the 1,4-di-loweralkyl compound wherein both R and R are lower alkyl, Further, asdiscussed above, this, 1,4-disubstituted compound can also be obtainedby heating a compound wherein R is lower alkyl and R is hydrogen with anexcess of lower alkyl halide.

Compounds of Formula II above wherein R is lower alkenyl can be obtaineddirectly from 2-(N-lower alkenyl)-aminobenzophenones. Alternatively,compounds of Formula II above wherein R is lower alkenyl can be preparedfrom the corresponding compounds of Formula II above wherein R ishydrogen by reacting the lastmentioned compounds with a lower alkenylhalide, e.g. allyl bromide, after first effecting the conversion thereofto its l-sodio-derivative with, for example, sodium hydride, sodiummethoxide and the like. The last-mentioned preparative procedure can beeffected in any suitable medium such as ether, benzene, alcohol ordioxane.

The direct synthesis of the benzodiazepinones by reaction of the2-amino-trifiuoromethylbenzophenones with an a-amino acid or estherthereof forms an important feature of the invention. According to thismethod, the ketone is heated with an a-amino acid or ester thereof suchas glycine or a glycine ester; for example a glycine lower alkyl estersuch as glycine ethyl ester, a-alanine or an a-alanine lower alkylester, and the like. The reaction is preferably effected in a solventsuch as pyridine, dimethylformamide, and the like. It is also preferableto have an ion of a strong acid present in the reaction mixture andtherefore it is convenient to use reagents in the form of the salt of astrong organic or inorganic acid, e.g. glycine hydrochloride, glycineethyl ester hydrochloride, oz-alanine hydrochloride, rat-alanine methylester hydrochloride or part of the pyridine as pyridine hydrochloride.

Benzodiazepin-one compounds corresponding to Formula IV above can alsobe produced by reacting a 2- amino-trifiuoromethylbenzophenonecorresponding to Formula I above, with an a-halo-lower alkanoyl-halide,preferably a chloro or bromo-lower alkanoyl chloride or bromide, such aschloracetyl chloride, bromoacetyl bromide, a-bromopropionyl bromide andthe like, to produce a Z-(a-halo-loweralkanoylamino)-trifluoromethylbenzophenone corresponding to the formulahalogen wherein R R and R have the same meaning as above, and R isselected from the group consisting of hydro gen and lower alkyl.

The compounds corresponding to Formula IX can then be directly cyclizedby reaction with ammonia to yield compounds corresponding to Formula IVabove or they can be reacted with ammonia so that the halogen atom isreplaced by the amino group yielding a Z-(a-aminolower alkanoylamino)trifluoromethyl benzophenone which then can be cyclized to a compoundcorresponding to Formula IV above. The 2-(a-amino-loweralkanoylamino)-trifiuoromethylbenzophenones and the method of cyclizingthem to compounds of Formula IV above are not a part of this inventionbut are disclosed herein in order that the present disclosure may becomplete.

Any of the compounds of Formulas I-IX above can be treated with an agentwhich introduces a nitro group into a position on one of the benzenerings thereof. Further, any nitro group present in any of the compoundsof Formulas I-IX above can be reduced to an amino group.

The term lower alkyl as used herein is intended to connote both straightand branched chain hydrocarbon groups such as methyl, ethyl, propyl,isopropyl and the like. The term lower alkenyl as employed throughoutthe specification is intended to represent a straight or branched chainmonoethylenically unsaturated hydrocarbon group such as allyl, propenyland the like. The term halogen represents all four forms thereof, e.g.chlorine, bromine, iodine and fluorine.

The benzodiazepin compounds corresponding to Formulas II and III above,which are inclusive of the compounds corresponding to Formulas IVthrough VIII above, are valuable as therapeutic agents. They are usefulas sedatives and anti-convulsants and can be used as tranquilizers andmuscle relaxants. These compounds can be administered parenterally ororally in therapeutic dosage forms with dosage adjusted to individualneeds in solid or liquid dosage forms such as tablets, capsules,suspensions, elixirs and the like. The compounds which are basic incharacter can be administered in the form of the medicinally acceptableacid addition salts and those with a tertiary nitrogen atom in the4-position can be administered in the form of their quaternary ammoniumsalt.

The following examples are illustrative of the invention but notlimitative thereof. All temperatures are in degrees centigrade.

Example 1 g. of sodium nitrite were added slowly with stirring to 460ml. of concentrated sulfuric acid. After heating to 70, a clear solution-was obtained. This solution was cooled and 200 g. of2-chloro-5-trifluoromethylaniline were slowly added at a temperaturebetween 10 and 20. The reaction mixture was stirred for one hour at 20and then poured onto a mixture of 200 g. of sodium chloride and 1.6 kg.of ice. Excess sodium chloride was filtered off. A solution of 280 g. ofzinc chloride in 300 ml. of water was added to the filtrate whereupon azinc chloride double salt of the corresponding diazonium compoundprecipitated. After standing overnight at 0, the double salt wasfiltered off and washed with a cold saturated salt solution.

To a solution of g. of sodium cyanide and 72 g. of cuprous cyanide in300 ml. of 'water were added with stirring and cooling with ice, 291 g.of the wet zinc chloride double salt. After the addition of 24 g. ofsodium carbonate, the mixture was first stirred for one hour at 20 andthen at 70 for an additional /2 hour. The reaction mixture was cooledand extracted with ether to obtain crude2-chloro-5-trifluoromethylbenzonitrile. The product 'was purified bysteam distillation and crystallization of the organic part of thedistillate from hexane to give the pure compound, M.P. 39-40".

Example 2 To a solution of phenyl magnesium bromide, prepared from 9.5g. of magnesium, 58.5 g. of bromobenzene and 500 ml. of anhydrous ether,was added with stirring a solution of 39 g. of2-chloro-5-trifluoromethylbenzonitrile in 200 ml. of benzene. 400 ml. ofsolvent were distilled off and the reaction mixture was then refluxedfor 16 hours. The Grignard complex was decomposed with 40 g. of ammoniumchloride and 200 g. of ice. The mixture was then extracted with benzene.2-chloro-5-trifiuoromethylbenzophenone imine hydrochloride wasprecipitated from the benzene solution by the addition of 40 ml. ofconcentrated hydrochloric acid. The product -was filtered off, washed'with benzene and dried in vacuo, M.P. 248-251", and upon furtherpurification melted at 250-262.

Example 3 60 g. of 2-chloro-5-trifiuoromethylbenzophenone iminehydrochloride were refluxed overnight with a mixture of 300 ml. oftoluene and 300 ml. of 25% sulfuric acid while elapse Example 4 2 g. of2-amino-5-trifluoromethylbenzophenone in 50 ml. of pyridine wererefluxed for 1 /2 hours with 2.0 g. of glycine ethyl esterhydrochloride. After that, another 1.0 g. of glycine ethyl esterhydrochloride in 2 ml. of pyridine were added. Then 3 ml. of the solventwere distilled otf.

Refluxing was continued for an additional 2 /2 hours. The.

reaction mixture was extracted with benzene, the organic layer waswashed with water and dried over sodium sulfate. After evaporation ofthe solvent, a crude oil was obtained which was dissolved in hexane.After 2 days at the precipitated pure crystalline 7-trifluoromethyl-5-phenyl-3H-1,4-benzodiazepin-2(lH)-one was filtered 01f. It melted at198-199".

By reducing 7-trifluoromethyl-5-phenyl-3H-1,4 benzodiazepin-2-(1H)-onewith one molar proportion of hydrogen in glacial acetic acid at roomtemperature and atmospheric pressure in the presence of platinum oxidecatalyst, 7-trifluorornethyl-5-phenyl-4,S-dihydro 3H 1,4benzodiazepin-2(1H)-one is obtained.

By using a-alanine methyl ester hydrochloride instead of the glycineethyl ester hydrochloride, 7-trifluoromethyl-3-methyl-5-phenyl-3H-1,4-benzodiazepin-2( lH)-one is obtained.

Example 6 13.3 g. of 2-amino-5-trifluoromethylbenzophenone in 60 ml. ofethanol were refluxed for 24 hours with 6 g. of hydroxylaminehydrochloride. The reaction mixture was adjusted to about pH 6 by theaddition of a solution of 12 g. of sodium acetate in 100 ml. of water.The mixture was then extracted with ether to yield an oil which, afterrepeated crystallization from a mixture of ether and hexane, gave2-amino-S-trifluoromethylbenzophenone oxime melting at 175177, whichupon further crystallization melted at 182183 (corr.).

Example 7 2.8 g. of the 2-amino-5-trifiuoromethylbenzophenone oximeobtained above were dissolved in 15 ml. of acetic acid and, afteraddition of 1.5 ml. of chloroacetyl chloride, kept for one hour at 20,then for two hours at 70. The mixture was diluted with ether and washedwith water. The ether solution was concentrated in vacuo and gave asolid residue which was crystallized from methylene chloride-ether toyield pure, yellow 2-chloromethyl- 4-phenyl-6-trifluoromethylquinazoline3-oxide, M.P. 149- 150.

Example 8 538 mg. of2-ch1oromethyl-4-phenyl-6-trifluoromethylquinazoline 3-oxide weredissolved in 20 ml. of ethanol, and after the addition of 5 ml. of 3 Nsodium hydroxide, the solution was kept for 4 hours at 25. Afteracidification with 6 ml. of 3 N hydrochloric acid, the reaction productwas extracted with ether. The ether solution was concentrated in vacuoand the residue crystallized from benzene to yield purified7-trifluoromethyl-5-phenyl-3H- 1,4-benzodiazepin-2(1H)-one 4-oxide, M.P.211-212", which upon further crystallization melted at 217-218" (corr.).

Example 9 1.60 g. of7-trifluoromethyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide weredissolved in .60 ml. of benzene, containing 0.30 g. of sodiumInethoxide. After the addition of a solution of 0.50 ml. ofdimethylsulfate in 20 ml. of benzene, the reaction mixture was refluxedfor 1 hour, then cooled. The organic layer was separated, washed withwater and dried over sodium sulfate. Evaporation of the solvent in vacuoyielded an amorphous crude, which was crystallized from ether-hexane togive pure 1-methyl-7-trifiuoromethyl-5-phenyl 3H 1,4benzodiazepin-2(1H)-one 4-oxide, in the form ,of small prisms, M.P.177l80, which upon recrystallization -melt ed at 184186 (corr.).

Example 10 1.0 g. of 1-methyl-7-trifluoromethyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide were dissolved in 20 ml. of chloroform.After addition of 0.3 ml. of phosphorus trichloride, the solution wasrefluxed for /2 hour. The reaction mixture was diluted with ether andwashed with sodium bicarbonate solution and water. After drying oversodium sulfate, the solvent was evaporated in vacuo to givel-methyl-7-trifluoromethyl-5-phenyl 3H 1,4 benzodiaZepin-2(lH)-one asthe residue.

Example 11 0.3 g. of 1-methyl-7-trifluoromethyl-5-phenyl-3H-1,4-benzodiazepin-2(1H)-one 4-oxide was dissolved in 15 ml. of methanol andhydrogenated at room temperature and normal pressure using Raney nickelas a catalyst. After one molar proportion of hydrogen had been absorbed,the catalyst was filtered off, and the solvent was evaporated to obtainthe same product as in Example 10.

Example 12 0.5 g. of2-chloromethyl-4-phenyl-fi-trifiuoromethylquinazoline 3-oxide wastreated with 10 ml. of a saturated solution of ammonia in methanol. Thereaction mixture was left for 5 hours at room temperature, then dilutedwith ether and washed 3 times with water. The ether solution wasseparated and dried over sodium sulfate. The solvent was evaporated invacuo and the residue was crystallized from benzene-hexane. The7-trifluoromethyl-2- amino-5-phenyl-3H-1,4-benzodiazepine 4-oxide wasobtained as white needles, M.P. 229-231, which upon furthercrystallization melted at 240242 (corr.).

Example 13 500 mg. of2-chloromethyl-4-phenyl-fi-trifluoromethylquinazoline 3-0xide werereacted for 5 hours at 25 with 10 ml. of a 40% solution of methylaminein methanol. The reaction mixture was diluted with water, then extractedwith ether. The ether solution was concentrated in vacuo and theresidual crude, 7-trifluoromethyl-2- methylamino 5phenyl-3H-1,4-benz0diazepine 4-oxide, was purified by crystallizationfrom ether-hexane to yield colorless crystals melting at 257-258, whichupon recrystallization melted at 264-265".

mg. of 7-trifluoromethyl-2-methylamino-5 phenyl- 3H-l,4-benzodiazepine4-oxide, dissolved in 5 ml. of methanol, were treated with 3 ml. of 0.1N hydrochloric acid at 25. The reaction mixture was evaporated at 40 invacuo and the residue was crystallized from methanolether to give thepure hydrochloride of 7-trifluoromethyl-2-methylamino-5-phenyl-3H-1,4-benzodiazepine 4-oxide in the form ofwhite prisms, M.P. 222 (with dec.).

Example 14 75.9 g. of sodium nitrite were added slowly with stirring to445 ml. of concentrated sulfuric acid at O10 C. After the addition wascompleted, the reaction mixture was allowed to stir without externalcooling, whereupon the temperature rose to about 70 C. and the solutionturned turbid. After cooling to 30 C., 206 g. of 2-nitro-4-trifluoromethyl-aniline were added in portions over a period of about2 hours, the temperature being kept at 30 to 35 C. Stirring wascontinued for an additional 1% hours at room temperature. Then, thereaction mixture was poured over 1.35 kg. of ice. A small amount ofinsoluble material was filtered off and the filtrate treated with 270 g.of zinc-chloride, dissolved in a small amount of water. After coolingfor several hours to C., the precipitated diazonium zinc chloride doublesalt was filtered off and washed with a small amount of saturated sodiumchloride solution. To a cold solution of 147 g. of sodium cyanide and89.5 g. of cuprous cyanide in 750 ml. of water, the wet diazoniumcompound described above was added in small portions. During theaddition, the tempera ture was kept below 20 C. After addition of 30 g.of sodium bicarbonate, the reaction mixture was stirred at roomtemperature for 2 hours. Then, it was heated for half an hour on a steambath to 70 C. After cooling, water and ether was added to the reactionmixture; then, it was acidified, filtered and the filtrate extractedwith ether the usual way to give an oil, which was purified bydistillation. The fractions between 85-110/ l-2 mm. Hg solidified andcontain the 2-nitro-4-trifluoromethylbenzonitrile.

Example 15 100 g. of 2-nitro-4-t1'ifluoromethylbenzonitrile weredissolved in 2.5 liters of methanol and hydrogenated at atmosphericpressure in the presence of 20 g. of wet Raney nickel catalyst. Thereaction was continued until 3 molar proportions of hydrogen wereabsorbed. The catalyst was filtered off and the methanol solution wasevaporated to dryness. The residue was crystallized from a mixture ofether and petroleum ether. The 4-trifluoromethyl-anthr-anilic acid amideformed colorless needles melting at 151- 152.

Example 16 68.5 g. of 4-trifiuoromethylanthranilic acid amide wererefluxed with 700 ml. of a 50% sulfuric acid solution for one hour, thenpoured onto ice. The precipitated reaction product was filtered otf andwashed with water. The 4-trifluoromethylanthranilic acid wascrystallized from a mixture of ethanol and water and then melted at 175.

Example 17 A solution of 23 g. of 4-trifluoromethylanthranilic acid in150 ml. of acetic anhydride was refluxed for one hour. Then the solventwas removed by distillation under reduced pressure and the residue wascrystallized from benzene-hexane to obtain2-methyl-7-trifluoromethyl-4H- 3,1-benzoxazin-4-one, M.P. 6870.

Example 18 A solution of phenylmagnesium bromide, prepared from 2.4 g.of magnesium, 15.2 g. of bromobenzene and 150 ml. of ether, was added toa solution of 18 g. of 2-methyl6-trifluoromethyl-4H-3,l-benzoxazin-4-one in 100 ml. of benzenewhile stirring and cooling with ice. The Grignard reagent was addedslowly over a period of one hour. After stirring for one additional hourat the reaction mixture was treated with ice and ammonium chloride. Thecrude reaction product was extracted with ether. The extract wasconcentrated in vacuo and the residue was refluxed for one hour with amixture of 100 ml. of 3 N sodium hydroxide and 100 ml. of methanol. Thereaction mixture was extracted with benzene. The benzene extract wasconcentrated in vacuo and the residual, crude 2-amino-4-trifluoromethyl-benzophenone was dissolved in hexane andpurified by chromatography using a 20 fold amount of neutral alumina(Brockrnann activity state III). Eluiion with a mixture of hexane-ether(1&1) and evaporation yielded yellow 2-amino-4-trifluoromethylben- 10zophenone which was recrystallized from hexane, M.P. 5556 (corr.).

Example 19 To a stirred solution of 9.1 g. (0.03 moles) of 1,3- dihydro5 phenyl-7-trifluoromethyl-ZH-1,4-benzodiazepin-2-one in 100 ml.dimethylformamide was added 1.6 g. (0.03 moles) of sodium methoxide. Thereaction mixture was stirred at room temperature for 20 minutes. 2.6 ml.(0.03 moles) of allyl bromide was added thereto. The stirring at roomtemperature Was continued for about 10 minutes. The reaction mixture wasthen heated to for 10 minutes and concentrated in vacuo to dryness. Theresidue was extracted with boiling ether. The ether extract wasconcentrated to a small volume and crystalline 1 allyl1,3-dihydro-5-phenyl-7-trifiuoromethyl-ZH-1,4- benzodiazepin-Z-one wasseparated by filtration. The product was recrystallized from a mixtureof ether and petroleum ether and formed colorless prisms melting at1265-1275".

Example 20 A solution of o-trifluoromethyl phenyl magnesium bromide wasprepared in the usual manner from 50.0 g. of o-bromo-benzo-trifluoride,5.55 g. of magnesium and 110 ml. of anhydrous ether. The Grignardreagent can also be prepared by reacting 39.7 g. ofo-chlorobenzotrifluoride with 5 .55 g. of magnesium in tetrahydrofurane.This solution was added with stirring at 20 C. over a period of 3 hoursto a solution of 33.0 g. of 2-methyl-4H-3,l-benzoxazin-4-one in 300 ml.of methylene chloride. The resulting dark but clear solution was left atroom temperature for 16 hours and was then poured over a mixture of g.of ammonium chloride and 600 g. of crushed ice. Extraction with ethergave a crude reaction product which was directly hydrolized by refluxingfor one hour in a mixture of 240 ml. of ethanol and 240 ml. of 3 Nsodium hydroxide. After standing overnight, the reaction mixture wasextracted with ether. The ether layer was washed with water andconcentrated in vacuo yielding an oil. This was purified in two portionsby chromatography on the 20-fold amount of neutral alumina (activitygrade III; e.g. containing 6% of water). Elution with petroleum etherand a mixture of petroleum ether (6070) and ether (9: 1) followed bycrystallization from a mixture of ether and hexane yielded2-amino-2'-trifluoromethylbenzophenone, melting at 9496 (yellow prisms).

Example 21 To a solution of 5.0 g. of2-amino-2'-trifluoromethylbenzophenone in 25 ml. of anhydrous ether,cooled to 0 C., 1.7 ml. of bromoacetylbromide was added with stirring; aprecipitation occurred and the yellow color of the solution graduallyfaded. The suspension containing2-bromoacetamido-2'-trifluoromethylbenzophenone (not isolated) wasstirred for half an hour at 0 C. and for two hours at room temperature.After that, 25 ml. of liquid ammonia was condensed into the flask, byintroducing ammonia gas and using an efficient dry ice-acetonecondenser. The resulting mixture was stirred and refluxed (B.P. ofliquid ammonia) for 3 hours. After taking off the condenser, the ammoniawas allowed to evaporate overnight. The reaction mixture was extractedwith ether (the ether layers being washed 3 times with water) andyielded crude 2-amino-2'- Z-trifluoromethylbenzoyl) acetanilide.Recrystallization from a mixture of 15 ml. of benzene and 15 ml. ofhexane gave the pure product, melting at 141-142 C. (colorless, rhombicplates).

4 Example 22 3.0 g. of 2-amino-2' (2 trifluoromethylbenzoyl)acetanilidewas heated in an open tube for 15 minutes to 200- 205 C., using an oilbath. Water was given off. On coolisolated) was stirred for half an hourat 0 C. and for two from a mixture of methanol and ether, gave crude5-(2 trifluoromethylphenyl)-3H-1,4 benzodiazepin 2(1H) one. The motherliquor was evaporated to dryness, disi Example 23 A solution ofm-trifiuoromethyl-phenyl magnesium bromide prepared from 5.55 g. ofmagnesium, 50.0 g. of m-bromo-benzotrifluoride and 110 ml. of anhydrousether was added with stirring over a period of 3 hours at 20 C. to asolution of 33.0 g. of 3-methyl-4H-3,1-benzoxazin-4- one in 300 ml. ofmethylene chloride. After stirring at room temperature for an additionalhalf hour, the reaction mixture was poured over a mixture of 50 g. ofammonium chloride and 500 g. of ice and allowed to stand overnight. Thecrude product obtained in the usual manner by extraction with ether andthe evaporation of the solvent was hydrolyzed by refluxing for one hourwith a mixture of 250 ml. of ethanol and 250 ml. of 3 N sodiumhydroxide. Upon addition of 200 ml. of water, a yellow precipitate wasformed. This was filtered off and washed with 50% ethanol and then etherand discarded. Ether treatment of the filtrate yielded an additionalamount of insoluble material which was filtered off. The ether solutionwas then separated from the aqueous layer, dried and concentrated invacuo. The residue was taken up in petroleum ether and chromatographedon 580 g. of neutral alumina (activity grade III; e.g. containing 6% ofwater). After elution of material with petroleum ether (60-70"), yellow2-amino-3-trifluoromethylbenzophenone could be eluted with a mixture ofpetroleum ether (60-70) and ether (9:1). Crystallization from a mixtureof ml. of ether and 50 ml. of petroleum ether (GO-70) yielded the pureamine, melting at 9799 C. (yellow needles).

Example 24 2.00 g. of 2-amino-3'-trifiuoromethylbenzophenone was treatedwith glycine ester hydrochloride as described in Example 5.Crystallization of the crude reaction product, using ether and benzene,gave a crude product melting between 200 and 205 C. This material wasdissolved in ml. of acetone, filtered through a column of 5 g. ofneutral alumina (activity grade II; e.g. containing 3% of water) andthen recrystallized from acetone-benzene to yield pure5-(3-trifluoromethylphenyl)-3H-1,4-benzodiazepin-2-(1H)-one, melting at204-205 C. (colorless, flat needles).

Example A solution of p-trifiuoromethyl phenyl magnesium bromide,prepared from 5.55 g. of magnesium, 50.0 g. of p-bromo-benzotrifluorideand 110 ml. of anhydrous ether, was added with stirring over a period of3 hours at 20 C. to a solution of 33.0 g. of2-methyl-4H-3,1-benzoxazin-4- one in 300 ml. of methylene chloride.After stirring at room temperature for an additional half hour, thereaction mixture was poured onto a mixture of 50 g. of ammonium chlorideand 500 g. of ice. The mixture was left overnight at room temperatureand then extracted with ether. The ether extract was concentrated andgave a crude material, which was hydrolyzed by refluxing for one hourwith a mixture of 300 m1. of ethanol and 300 ml. of 3 N sodiumhydroxide. Extraction with petroleum ether (60 70) yielded a yellowsolid. Chromatography of the mate-' rial soluble in petroleum ether on200 g. of neutral alumina (activity grade II; e.g. containing 3% water)gave, on elution with petroleum ether (6070) and a petroleum ether(6070)-ether (9:1) mixture, yellow solid 2-amino-4'-trifiuoromethylbenzophenone. Crystallization from 150 ml. of hezane yielded a pureproduct (yellow needles). An analytical sample melted at 99- 100 C.

Example 26 2.00 g. of 2-amino-4-tritluoromethyl-benzophenone was treatedwith glycine ester hydrochloride as described in Example 5.Crystallization of the crude reaction product from a mixture of etherand hexane yielded the crystalline 5-(4-trifiuoromethylphenyl) 3H-l,4benzodiazepin 2 (lH)-one. Recrystallization from acetone-benzene gavethe pure compound, melting at 219220 C. (colorless needles).

Example 27 7.3 g. of5-(2-trifluoromethylphenyl)-3H-1,4-benz0diazepin-2(1H)-one weredissolved at 0 in 58.4 ml. of concentrated sulfuric acid. To this, overa period of about 15 minutes, 3.22 g. of potassium nitrate wereaddedwith stirring. After keeping the reaction mixture for 30 minutes at0, it was allowed to stand for one hour at 25. Finally, it was heated to50 for 3 hours. After standing overnight at 25, the yellow solution waspoured over 250 g. of ice and the precipitate obtained, filtered andthoroughly washed with diluted ammonium hydroxide solution, dilutedacetic acid and water. Crystallization from acetone-benzene of the thusobtained crude product afforded the 7 nitro 5 (2 trifluoromethylphenyl)3H 1,4- benzodiazepin-2(1H)-one. From the mother liquor and thefiltrate, a second crop could be obtained. An analytical sample wasprepared by recrystallization from acetonemethanol. Slightly yellowprisms (hexagonal), melting at 233-234, were obtained.

This compound is useful as a muscle relaxant and has shown itself to beparticularly advantageous in this regard, due to the uterine relaxantproperties evidenced thereby.

Example 28 26.5 g. of 2-amino-5-trifiuoromthylbenzophenone weredissolved in 250 ml. of anhydrous ether and 7.9 ml. of pyridine. Theresulting solution was stirred and cooled to 0 C. and then treated overa period of 30 minutes with a solution of 23.2 g. of bromoacetyl bromidein 50 ml. of anhydrous ether. After stirring for another half hour at 0C., the resulting suspension was stirred for 3 hours at roomtemperature. Water was then added, the ether layer was separated andconcentrated in vacuo. The oily residue (39.2 g.) was crystallized froma mixture of ml. of benzene and m1. of hexane yielding a first crop of2-bromoacetamido-S-trifluoromethylbenzophenone in the form of needles.From the mother liquor, a second crop could be obtained.Recrystallization from benzenehexane gave an analytical sample, meltingat 103-104 C.

Example 29 5.0 g. of 2-bromoacetamido-5-trifiuoromethylbenzophenone weredissolved in ml. of anhydrous ether and added over a period of 1 hourwith stirring to 50 ml. of dry, liquid ammonia. The resulting solutionwas stirred for 5 hours at the reflux temperature of ammonia, a DryIce-acetone condenser being used. This was then replaced with aconventional water-condenser and the ammonia allowed to distill offovernight. The resulting suspension, afterstanding for 5 days at roomtemperature, was diluted with water and extracted with ether. The etherextract was concentrated in vacuo to give crude2-aminoacetamido-5-trifiuoromethylbenzophenone. Crystallization from 6ml. of benzene and 15 ml. of hexane gave a pure product, melting at97-99 C.

Example 3 0 1.00 g. of Z-aminoacetamido-S-trifluoromethylbenzophenone in10 ml. of pyridine were refluxed for two hours. Evaporation of thesolvent and crystallization of the residue from benzenehexane gavecolorless prisms of 5 phenyl 7 trifluoromethyl 3H 1,4 benzodiazepin-2(1H)-one, melting at 205206 C.

1 3 Example 31 100.0 g. of 2-chloro-5-trifluoromethylbenzonitrile werestirred and refluxed for one hour in a solution prepared from 200 g. ofsodium hydroxide and 400 ml. 'of water. After cooling, the suspensionwas diluted with-2 liters of water and extracted with ether to give aneutral, red oil, which was discarded. The aqueous alkaline layer wasthen acidified (Congo-red) with sulfuric acid and extracted with ether.After evaporation of the ether a crude, solid material, melting at 82-83C., was obtained. This was heated with 300 ml. of hexane to 60 C. forminutes and then cooled to 0 C. After filtration on a suction funnel,2-chloro-S-trifluoromethylbenzoic acid was obtained. Recrystallizationfrom hexane gave an analytically pure sample; colorless plates, meltingat 9394 C.

Example 32 A mixture of 100.0 g. of 2-chloro-5-trifluoromethylbenzoicacid and 3.40 ml. of thionyl chloride was stirred and refluxed for 4hours. After evaporation of the reagent in vacuo, the crude2-chloro-S-trifluoromethylbenzoic acid chloride was fractioned in vacuo,using a cm. Vigreaux column, B.P. 5961/1 mm. (colorless liquid).

Example 33 First, a solution of o-trifluoromethyl phenyl magnesiumbromide was prepared in the usual way using 13.5 g. of magnesiumturnings, 255.0 ml. of anhydrous ether and 122.5 g. ofo-bromo-benzo-trifluoride. Then, over a period of 30 mins., a solutionof 120.0 g. of 2-chloro-5-trifluoromethylbenzoic acid chloride in 1liter of benzene was added with stirring at C. to the Grignard solution.After stirring for an additional minutes at 20 C., a part of thesolvent, e.g. all of the ether, was distilled off until the distillationtemperature reached 78 C. The reaction mixture was then refluxed for 3hours. Itwas left at room temperature overnight and was then poured overa mixture of 100 g. of ammonium chloride and 500 g. of ice. Afterstanding for 1 hour, it was extracted with ether. The ether layers werewashed with water, 3 N sodium hydroxide and again with water.Evaporation of the solvent in vacuo after drying over sodium sulfateyielded an oil, which was purified in 2 portions by chromatography, on atotal of 2.4 kg. of aluminum oxide (activity grade II). Elution withhexane (25.4 liters total) and ether-hexane- (911)-and (4:1)mixture (6liters total) yielded 2- chloro-2,5-bis-(trifluoromethyl)-benzophenone.This was recrystallized from 200 ml. of hexane. Recrystallization fromhexane gave an analytically pure sample, (colorless needles), melting at4950 C.

Example 34 A mixture consisting of 50.0 g. of 2-chloro-2',5-bis-(trifluoromethyl)-benzophenone, 300 ml. of dioxane, 300 ml. ofconcentrated ammonium hydroxide (58% NH OH, corresponding to 28-30% NHand 5 g. of cuprous chloride was heated to 140 C. for 10 hours in anautoclave. The reaction mixture was extracted with ether yielding anoil. This was purified as follows: the crude reaction product wasdissolved in 800 ml. of hexane, filtered through cotton into a 2 literErlenmeyer flask, placed in an ice-bath. 200 ml. of 50% (by weight)sulfuric acid were added and the mixture allowed to stir for 30 minutes.This caused a voluminous precipitation (amine sulfate) which wascollected with suction on a sintered glass funnel. The solid materialthus-obtained was introduced into 200 ml. of 3 N sodium hydroxide inorder to generate the free amine. This was extracted with ether in theusual way; an oil was obtained, which was further purified by dissolvingit in 500 ml. of hexane and filtration through 50 g. of aluminum oxide(activity grade I). The column was washed 3 times with 100 ml. of hexaneeach. The hexane eluates were combined, concentrated to about 80 ml. andkept overnight at 0 C. Thus, light yellow prisms of 2 amino2',5-bis-(trifluoromethyl)-benzophenone were obtained. Recrystallizationfrom hexane gave an analytically pure sample melting at 7678 C.

Example 35 11.64 g. of 2-amino-2,5-bis-(trifluoromethyl)-benzophenonedissolved in 56 ml. of anhydrous ether and 2.84 ml. of pyridine, weretreated at 0 C. with 3.0 ml. of bromoacetylbromide. An immediateprecipitation occurred containing the 2-bromoacetamido derivative whichwas not isolated. After stirring the reaction mixture first for one hourat 0 C., then for 3 hours at 25 C., 50 ml. of liquid ammonia wereintroduced into the reaction flask, using a Dry Ice-acetone condenser.After stirring for 3 hours at the reflux temperature of liquid ammonia,the Dry Ice condenser was replaced with a conventional condenser and theammonia allowed to evaporate overnight. Some more ether and water wasadded to the residue. The ether layer was separated and concentrated invacuo. The oily residue was dissolved in a mixture of 50 ml. of benzeneand 50 ml. of hexane and chromatographed on 280 g. of aluminum oxide(activity grade III). Starting material was regenerated using 3 times300 ml. of benzenehexane-(1:l)-mixture as an eluant. Then, with purebenzene, followed with ether, 2-aminoacetamido-2',S-bis-(trifluoromethyl)-benzophenone was eluted. Crystallization frombenzene-hexane and recrystallization from benzene-hexane gave slightlyyellow, cubic prisms, melting at 108-109 C.

Example 36 3.33 g. of 2-aminoacetamido-2',5-bis-(trifluoromethyl)-benzophenone were heated in an open tube to 203205 C. for 30 minutes. Atthe beginning, the molten material bubbled strongly. The gas evolutionhad almost completley stopped after 30 minutes. Upon cooling, a glasswas obtained. This was dissolved in warm benzene and chromatographed ong. of aluminum (activity grade III). Elution with 300ml. of benzene gavean oil, which was discarded. Elution with a benzene-ether mixture (1:1)yielded an oily material, which crystallized readily upon addition to afew drops of benzene. It was further purified by dissolving in ether andextraction with 1 N hydrochloric acid. The ether extract was thencrystallized from a small amount of ether to give2',5-bis-(trifluoromethyl)- 1,4-benzodiazepin-2(1H)-one. An analyticalsample, prepared by recrystallization from benzene-hexane, melted at226227 C. (colorless plates).

Example 37 11.25 g. of o-bromobenzotrifluoride was converted to theGrignard reagent in the usual way with 1.22 g. of magnesium and 200 cc.of dry ether. The solution was then added dropwise with cooling andstirring to 9.78 g. of 6-chloro-2-methyl-3,l-benZoxazin-4-one dissolvedin cc. of benzene and 50 cc. of ether. The resulting solution wasstirred for 1 hour at room temperature, then cooled in an ice bath andthe Grignard complex decomposed with 50cc. of 10% hydrochloric acid. Theorganic layer was separated and dried over anhydrous potassium carbonatefor 3 hours. The solvent was then distilled oif and the residue treatedwith a solution of 7 cc. of concentrated hydrochloric acid in 40 cc. ofethanol. After refluxing for 1 hour, the solvents were distilled off andthe residue treated with 20 cc. of water. A yellow solid separated.After drying, it was crystallized from hexane, yielding2-amino-5-chloro-2'-(trifluoromethyl)benzophenone which melted at 9799C.

Example 38 8.9 g. of bromoacetyl bromide was added dropwise to asolution of 13.3 g. of 2-amino-5-chloro-2-(trifluoromethyl)-benzophenonein 250 cc. of dry ether. After the addition, the solution was stirredfor 1 hour and the solvent removed. The residue was crystallized fromhep- 1 tane, yielding5-chloro-2-bromoacetamido-2-(trifluoromethyl)benzophenone melting at139-l41 C.

Example 39 4.2 g. of5-chloro-2-bromoacetamido-2'-(trifiuoromethyl)benzophenone was added to100 cc. of liquid ammonia containing 50 cc. of ether. The mixture wasstirred overnight during which time the ammonia evaporated. Water wasadded to the residue and the solid filtered. The product,5-chloro-2-glycylamino-2'-(trifiuoro methyl) benzophenone, wascrystallized from alcohol and melted at 1l4-l16 C.

Example 40 2.4 g. of 5-chloro-2-glycylamino-2'-(trifluoromethyl)-benzophenone was dissolved in cc. of pyridine and the solution refluxedfor 10 hours. The pyridine was distilled off and the residue wasrepeatedy crystallized from heptane-benzene and the product,7-chloro-5-(2-trifluorornethyl-phenyl)-3H-l,4-benzodiazepin-2(1H)-one,melted at 190192 C.

Example 41 4.97 g. of 7-nitro-5-(Z-trifiuoromethyl-phenyl)-3H1,4-benzodiazepin-2(1H)-one was dissolved in a cold solution of sodiummethoxide obtained from 350 mg. of sodium and 50 ml. of anhydrousmethanol. The solution was stirred at room temperature for 30 minutesafter which 5 ml. of methyl iodide was added and stirring continued for3 hours. The solution was then permitted to stand at l5 for severalhours during which time a crystalline precipitate formed. Theprecipitate was filtered ofi, washed with water and with ether, andcrystallized from acetone to yield 1methyl-7-nitro-5-(2-trifiuoromethyl-phenyl)-3H-l,4-benzodiazepin-2(lH)-one as almost colorless prisms melting at198199 C.

Example 42 20.0 g. of 2 chloro 5 trifluoromethylbenzophenone weredissolved in 300 ml. of a saturated (at methylamine solution inmethanol. 10.0 g. of cuprous chloride were added and the resultingmixture heated to 140 for a period of 10 hours in an autoclave. Theresulting reaction mixture was concentrated in vacuo to about 100 m1.diluted with water, and extracted with ether. The ether extract yieldedafter concentration 18.4 g. of an oil which was dissolved in hexane andpurified by chromatography on 400 g. of alumina (Woelm, grade III). Theelution was carried out first with four 400 ml. fractions of hexane. Thenext three fractions (400 ml. each) were obtained using a hexane-ethermixture (9:1) as the eluant.

Fraction 1 of the chromatogram, upon crystallization from ether-hexane,gave a,a,a-trifiuoro-N-methyl-2-(amethyliminobenzyl)-p-toluidine as longcolorless needles, melting at 100-101.

Fractions 6 and 7 of the chromatogram, upon crystallization from 5 ml.of hexane gave oc,oc,a-triflll0r0-N- methyl2-(amethyliminobenzyl)-p-toluidine as colorless prisms melting at l20122.

The two samples ofoc,oc,zx-tIlfiUOIO-N-mthYl-Z-(atmethyliminobenzyl)-2-toluidine, withdiffering melting points, obtained above from fractions 1 and 6 and 7 ofthe chromatogram, represent isomers of the same compound.

Example 43 500 mg. of each of the isomers of u,a,a-trifluoro-N-methyl-Z-(a-methyliminobenzyl)-p-toluidine in 10 ml. of toluene wastreated with 2.5 ml. of water and 2.5 g. of concentrated sulfuric acid.The reaction mixture was extracted with ether and washed with water and3 N NaOH solution. Evaporation of the solvent followed bycrystallization from petroleum ether yielded Z-methylamino-S-trifiuoromethylbenzophenone, melting at 74-75 (yellow needles).

16 Example 44 A mixture, consisting of 50.0 g. of2-chloro5-trifiuoromethylbenzophenone, 10.0 g. of cuprous chloride and500 ml. of a saturated solution of methylamine in methanol was heated to140 for 10 hours in an autoclave. The mixture was concentrated, dilutedwith water and extracted with ether. The ether extract yielded afterconcentration 45.0 g. of crude reaction product, which partiallysolidified. Crystallization from 150 ml. of hexane gave a first crop.From the mother liquors, two more crops wereobtained. v

For the purpose of hydrolysis, these 3 fractions were combined andrefluxed for 15 minutes with vigorous stirring in a mixture of 260 ml.of toluene, 120 ml. of water and 120 g. of concentrated sulfuric acid.After cooling, the two layers were separated, the acid layer then beingextracted with hexane. The toluene layer and the hexane extract werecombined, washed 3 times with 3 N NaOH solution and dried over sodiumsulfate. Evaporation of the solution in vacuo, followed bycrystallization of the residue from 200 ml. of petroleum ether at 0,yielded 2 methylamino-S-trifiuoromethylbenzophenone melting at 7475.

Example 45 3.5 g. of 7-nitro-5-(2-trifluoromethylphenyl)-3H-l,4-benzodiazepin-2(lH)-one was suspended in 50 ml. of methanol andhydrogenated at room temperature and normal pressure, using Raney nickelas a catalyst. Approximately 750 ml. of hydrogen was consumed in about 2hours. The resulting solution was filtered free of the catalyst and thefiltrate concentrated to a volume of about 20 ml. Upon cooling, thesolid reaction product, 7-amino-5-(2-trifluoromethylphenyl)-3H-1,4-benzodiazepin 2(lI-I)- one, wasobtained. The material was dimorphic and had melting points at 221-222,and after crystallization from benzene, at 197-198.

Example 46 1 g. of 1-methyl-7-nitro-5-(2-trifiuoromethylphenyl)-3H1,4-benzodiazepin-2(lH)-one was hydrolyzed by refluxing it for 2 hoursin a mixture consisting of 5 ml. of concentrated hydrochloric acid, 5ml. of water and 10 ml. of ethanol. Extraction with ether and petroleumether gave a solid product. The mother liquor was concentrated in vacuo,a yellow oil obtained, and said oil purified by chromatography, using 15g. of alumina (Giulini, activity grade IH).) Elution with petroleumetherbenezene mixtures, 9:1 and 4:1, yielded crude reaction product, 2methylamino-5-nitro-2'-trifiuoromethylbenzophenone, as a yellow oil. Theoil was crystallized in ether-petroleum ether to yield pale yellowprisms which melted at 118-119".

Example 47 To a stirred solution of 19 g. of2-amino-2-trifluoromethyl-benzophenone in 200 cc. of acetic acid cooledin an ice bath to about 10, a solution of 11.46 g. of bromine in cc. ofacetic acid was added dropwise over a period of ten minutes. After theaddition had been completed the mixture was allowed to stir for anadditional five minutes at 10 and then the cooling bath was removed andthe reaction mixtureallowed to reach room temperature over a period of20 minutes. A white hydrobromide salt precipitated and was filtered off,washed with cc. of ether, dissolved in water and made alkaline withammonium hydroxide. The product was then extracted with methylenechloride (3X 50 cc.). The organic layers were combined, dried overanhydrous sodium sulfate, filtered and the solvent removed to give2-amino-5-bromo-2'- trifiuoromethyl benzophenone which uponrecrystallization from ethanol formed yellow needles melting at 93-94. Afurther crop of product was obtained by extracting the acetic acidfiltrate with methylene chloride 17 (4X 50 cc.), washing the combinedextracts with ammonium hydroxide (2X 50 cc.), water (3X 50 cc.), dryingover anhydrous sodium sulfate, filtering, removal of the solvent andrecrystallization of the residue from ethanol.

The same product could also be obtained by converting 35 g. ofo-chlorobenzotrifluoride to the Grignard reagent in the usual way with4.63 g. of magnesium and 30 cc. of dry tetrahydrofuran. The solution wasdiluted with 30 cc. of tetrahydrofuran and then added dropwise undernitrogen with cooling and stirring to 30 g. of 6-bromo-2-methyl-4H-3,l-benzoxazin-4-one dissolved in 200 cc. of dry toluene. Theresulting solution was stirred for 1 hour at room temperature, thenrefluxed for 1 hour, cooled in an ice bath and the Grignard complexdecomposed with 36 cc. of 5 N hydrochloric acid. The mixture was thendiluted with ether, washed with water, and then with aqueous ammonia.The organic. layer was separated, concentrated in vacuo and the residuerefluxed for 1 hour with a mixture of 50 cc. of concentratedhydrochloric acid in 50 cc. of ethanol. Then the solvents were distilledoff and the residue treated with 20 cc. of water whereupon a solidseparated. After drying, it was crystallized from hexane yielding2-amino-5-bromo-2'-trifluoromethylbenzophenone melting at 92-94".

A solution of 21.9 g. of Z-amino-5-bromo-2'-trifluoromethyl-benzophenonewas dissolved in 250 cc. of ether and treated with 13.8 g. ofbromoacetyl bromide. After the addition, the mixture was stirred for 1hour and the solvent removed. The residue was crystallized from methanolyielding 5 bromo-Z-bromoacetamido-2'-trifluoromethyl-benzophenone aswhite prisms melting at 140.5- 141.5

26.4 g. of 5 bromo-Z-bromoacetamido-2'-trifiuoromethyl-benzophenone wasadded to 750 cc. of liquid ammonia and the mixture was warmed gently onthe steam bath to facilitate evaporation of the ammonia. The residue wasthen partitioned between 200 cc. of methylene chloride and 300 cc. ofwater. The layers were separated and the organic layer washed with water(3X 50 cc.), saturated brine (3 X 25 cc.), dried over anhydrous sodiumsulfate, filtered, and evaporated to dryness. Recrystallization of theresidue from acetone gave 5-bromo-2-aminoacetamido-2'-trifluoromethyl-benzophenone, as a crystalline material, and an oilyresidue. The crude aminoacetamido compound was not further purified butwas recombined with the residue, dissolved in a mixture of 1200 cc. ofpyridine and 100 cc. of benzene, and refluxed using a fractionatingcolumn equipped with a Dean-Stark head. Water, formed in thecyclization, was removed by azeotropic distillation. After thetheoretical amount of water had been collected (36 hours), thepyridine-benzene solution was evaporated under reduced pressure to yield7- bromo 5-(a,a,u-trifluoro-orthotolyl)-3H-l,4-benzodiazepin-2(lH)-one-,which upon recrystallization from acetone/hexane formed white prismsmelting at 183-185 The 5 bromo2-aminoacetamido-2'-trifluoromethylbenzophenone mentioned above is not apart of this invention but its preparation is disclosed above in orderthat the present disclosure may be complete.

Example 48 A solution of 26.5 g. of 7-trifluoromethyl-4,5-dihydro-5-pheny1-3H-l,4-benzodiazepin-2(1H)one in 100 ml. ofN,N-dimethyl-formamide was stirred and refluxed for 1 hour with 5.14 g.of sodium methoxide (added in the form of a methanolic solutioncontaining 4.35 moles of sodium methoxide per cc. of solution). Thesodio derivative thus formed was treated with 123 g. of methyl iodideand the solution refluxed for a further 2 hours. After the excess methyliodide had been distilled off the reaction mixture was poured into 1,000ml. of water and extracted four times with 150 mL-portions of methylenechloride. The extracts were combined, treated with decolorizing carbon,dried over anhydrous sodium sulfate and filtered. Removal of the solventand recrystallization of the residue from hexane gave7-trifluoromethyl-l,4-dimethyl 4,5 dihydro5-phenyl-3H-1,4-benzodiazepin-2 (lH)-one as white needles melting at77-79.

Example 49 5-(2-trifluoromethylphenyl) 3H 1,4 benzodiazepin- 2(lH)-'one(60.8 gm.) was added at 20 to a solution of sodium methoxide, preparedfrom sodium (5.06 gm., 0.22 gram-atom) and anhydrous methanol (500 ml.).-The mixture was stirred for 15 minutes at room temperature, duringwhich time all the solids dissolved. Methyl iodide (40 ml.) was thenadded dropwise to the stirred solution during 20 minutes and stirringwas continued for a, further 3 hours at room temperature. The solutionwas concentrated in vacuo at 25 and water (900 ml.) added to theresidue. The mixture containing the resulting precipitate was extractedwith methylene chloride. The extract was washed with water, dried overanhydrous magnesium sulfate and evaporated, to give the crude product asa green gum which rapidly crystallized. Recrystallization fromethanol-water, with addition of decolorizing carbon, gave blue crystals.Decolorization of the product was readily effected by dissolving it inmethylene chloride and filtering the resulting solution through a shortcolumn of Woelm neutral alumina, activity V (400 -gm.). Evaporation ofthe eluates and recrystallization of the resulting residue from aqueousethanol, with addition of decolorizing carbon, gavel-methyl-S-(Z-trifluoromethylphenyl)- 3H-l,4-benzodiazepin-2(1H) one asvery pale yellow crystals, melting at 137138. Further crops obtainedfrom the mother liquors were purified by the above method and uponrecrystallization from aqueous ethanol yielded colorless rhombs, meltingat -137.

Example 50 5.3 g. of 2-amino-S-trifiuoromethylbenzophenone was dissolvedin 25 m1. of anhydrous ether and 1.60 ml. of pyridine. The resultingsolution was cooled to 0 and treated with a solution of 1.70 ml. ofchloroacetyl chloride in 10 ml. of anhydrous ether whereupon avoluminous precipitation occurred. After stirring for 1 hour at 0 andone hour at 25 the reaction mixture was diluted with water, the etherlayer separated, and concentrated in vacuo. The residue was crystallizedfrom a mixture of ether and hexane yielding2-chloro-2'-benzoyl-4-trifiuoromethyl-acetanilide as needles melting at1l5116.

Example 51 A solution of 2.1 g. of 7-l11tI0-5-(a,ot,a-tfifiuOr0*O-tolyl)-3H-1,4-benzodiazepin-2(1H)-one in a mixture of 35 ml. of ethanoland 35 ml. of 3 N hydrochloric acid was refluxed for 13 hours. Thereaction mixture was left at room temperature for 48 hours and thecrystalline product filtered off. Upon being recrystallized from ether,the product 2-amino-5-nitro-2'-trifluoromethylbenzophenone formed yellowrhombic plates melting at 1 64-5".

What is claimed is:

1. A compound selected from the group consisting of those represented bythe formula wherein A represents a carbon nitrogen grouping whichcompletes the seven-membered diazepine ring and which is selected fromthe group consisting of R is selected from the group consisting ofhydrogen, lower alkyl and lower alkenyl; R and R each represent a memberof the group consisting of hydrogen and lower alkyl; R; istrifiuoromethyl and R is selected from the group consisting of hydrogen,halogen, nitro, amino and trifiuoromethyl; and acid addition saltsthereof with pharmaceutically acceptable acids.

2. 5-(Z-trifiuoromethylphenyl)-3H-1,4-benzodiazepin-2 (1H)-one.

3. 7 nitro 5 (2 trifluoromethylphenyl) 3H 1,4- benZodiazepin-2(1H)-one.

4. 1 methyl 7 nitro 5 (2 trifluoromethylphenyl)- 3H-1,4-benzodiazepin-2(1H) -one.

5. A process for the production of compounds represented by the formulawherein R and R are selected from the group consisting of hydrogen,halogen, nitro, amino and trifiuoromethyl; and at least one of R and Ris trifiuoromethyl which comprises reacting a compound of the formulawherein R and R have the same meaning as above, with a member of thegroup consisting of alkali metal hydroxide and alkaline earth metalhydroxide.

6. A process for the production of compounds represented by the formulawherein R and R are selected from the group consisting of hydrogen,halogen, nitro, amino and trifiuoromethyl; and at least one of R and Ris trifiuoromethyl which comprises reacting a compound of the formula.

wherein R and R have the same meaning as above, with a member of thegroup consisting of alkali metal 0 hydroxide and alkaline earth metalhydroxide.

References Cited Yale J. Med. and Pharm. Chemistry vol. 1, No. 2, pp.121-133 (1959).

HENRY R. JILES, Primary Examiner.

R. T. BOND, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION ?atent No.3,412,086 November 19, 1968 Gabriel Saucy et al.

It is certified that error appears in the above identified patent andthat said Letters Patent are hereby corrected as shown below:

Column 10, line 73, cancel isoloted) was stirred for half an hour at 0C. and for two" and insert ing, a brown glass was obtained which,

an crystallization Signed and sealed this 7th day of April 1970.

(SEAL) Attest:

Edward M. Fletcher, Jr.

WILLIAM E. SCHUYLER, JR.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF THOSE REPRESENTED BYTHE FORMULA